Hepatitis B virus (HBV) can cause severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in 0.5-1 million deaths every year. Most chronic HBV carriers acquired the virus early in life from their infected mothers. In contrast to the mother-to-child transmission (i.e., vertical transmission), patients who acquired HBV from unrelated inviduals (i.e., horizontal transmission) will usually develop self-limited acute infection. Why vertical transmission leads to chronic infection whereas horizontal transmission leads to self- limited acute infection was unclear. Our recent studies indicated that HBV in the mothers could suppress anti- HBV immunity in her children to promote HBV persistence in the latter. HBV has a very narrow host range, which has greatly hampered its research. We have recently developed a mouse model to study the maternal effect on HBV persistence in her offspring. By crossing female hemizygous HBV transgenic mice to male nave mice, we obtained non-transgenic mouse pups. When these non-transgenic mouse pups were injected with the HBV genomic DNA by hydrodynamic injection, the HBV replication persisted in the mouse liver for up to 28 weeks. This is in contrast to control mice born to non-transgenic mothers, which cleared HBV after 3-4 weeks of HBV DNA injection. Our further studies indicated that maternal HBV could condition hepatic macrophages of the offspring, which would undergo M2 polarization to suppress HBV-specific CD8+ T cells after the introduction of HBV into the mouse liver. The goal of this application is to continue our previous studies to further understand the maternal effect on offspring immunity against HBV. Specifically, we will determine how HBV in the mother impacts HBV-specific CD8+ T cells and hepatic macrophages of the offspring. We will also determine whether and how maternal HBV affects the myeloid-derived suppressor cells (MDSCs) of the offspring and the possible roles of MDSCs in the suppression of anti-HBV immunity in the offspring. Finally, we will investigate the possible effect of gut microbiota and their metabolites, specifically butyric acid, on HBV replication and anti-HBV immunity of the offspring. The proposed studies will provide important information for us to understand the mechanism of HBV persistence after its mother-to-child transmission and facilitate the development of novel therapeutic options for chronic HBV patients.